The goal of this application is to advance our understanding of the physiological roles of the intestinal bile acid transporters and their relationship to intestinal and metabolic disease. Bile acids play critical roles in the intestinal absorption of fats and fat-soluble vitamins, gut anti-microbial defenses, and as signaling molecules to modulate lipid and glucose metabolism. By regulating the flux of bile acids in the enterohepatic circulation, bile acid transporters control the compartmentalization of bile acids and modulate their physiological and pathophysiological actions. In the previous funding period, we demonstrated the importance of the Organic Solute Transporter Ost?-Ost? for maintenance of the enterohepatic circulation and bile acid homeostasis. The studies proposed in this renewal application will focus on expanding our understanding of the physiological roles of the intestinal bile acid transporters and their relationship to intestinal and metabolic disease. This includes identifying the mechanisms responsible for the intestinal adaptive response in the Ost? null mice, and the mechanisms by which blocking intestinal bile acid absorption protects against the development of high fat diet-induced obesity and metabolic syndrome. The studies in Specific Aim 1 are designed to further elucidate the in vivo functions of Ost?-Ost? by determining the mechanisms responsible for the intestinal adaptive response in Ost? null mice. Our studies demonstrated that regulation of bile acid and lipid metabolism is differentially affected by disruption of intestinal bile acid absorption at the apical versus basolateral membranes. Based on this work, the studies in Specific Aim 2 are designed to define the roles of ileal FGF15 expression and bile acid flux in the anti-obesity and hypoglycemic effects associated with interruption of the enterohepatic circulation of bile acids. The long-term goal of this work is to understand the role of bile acids in human gastrointestinal and metabolic disease, and translate those insights into new preventive measures and therapies.